We have cloned and functionally identified cDNAs encoding the proteins SAT1 and SAT2 that are the first members of the system A family of Na+-dependent neutral amino acid transporters. Transport of system A substrates, such as glutamine, and alanine, in many cell types are highly regulated since these amino acids play important roles in neurotransmission, energy generation and in nitrogen metabolism. The identification of SAT1 and its neuron-specific expression is an unexpected discovery and suggests an important and unique role of SAT1 in synaptic transmission. The electrogenic uptake of these amino acids in peripheral organs is mediated by SAT2, and in neurons, SAT2 may provide alanine, as a nitrogen donor to alpha-ketoglutarate, to generate a metabolic pool of glutamate. Since glutamine is a critical precursor for neurotransmitter glutamate via the glutamate-glutamine cycle, it is reasonable to propose to test the hypothesis that these transporters play key roles in regulating the synthesis of the major excitatory transmitter in the brain. The purpose of this proposal is to study the regulation of these genes in glutamatergic neurons at the level of protein synthesis, as well as at the level of cycling between cellular compartments, in response to physiological and pathophysiological conditions, and to determine whether SAT1 and SAT2 are potential targets to modulate presynaptic glutamate synthesis and eventual exocytotic release.